Age is the major risk factor for a majority of the leading causes of death in the US including heart disease, cancer, stroke, and dementia. With a rapidly aging population pushing the boundaries of what our health care system can absorb, there has been an unprecedented interest in aging and longevity from the public, funding bodies, and industry. I believe that based on dramatic technological advances in chemical biology and empirical findings advanced in part by our group, the time is right to ask some of the fundamental questions about aging: what controls organismal aging? Does it start in one tissue and spread to another? Or does aging start in one cell type, such as in stem cells or senescent cells, and spread to other cells and tissues? Or does it start simultaneously in all cells, driven y aging mitochondria, by failures in DNA or protein maintenance, or other mechanisms? The proposed research will try to address these questions and follows from our groundbreaking discovery that soluble, heat labile factors in blood plasma are sufficient to accelerate brain agin or regenerate and rejuvenate old brains. These and studies with heterochronic parabiosis by others provide the foundation for my proposal by demonstrating that soluble factors carry information about the biological age of an organism, that soluble factors can actively modulate aging, and that aging is malleable and possibly reversible. I will take advantage of the extraordinary developments in chemical biology, which allow for the orthogonal (i.e. independent, causing no interference) introduction of genetically encoded, non-canonical amino acids into living organisms and the subsequent detection of the proteins into which they are incorporated. This revolutionary concept is based on a rewired translation in which the genetic code is expanded resulting in the production of modified proteins, which can be chemically identified. We will generate transgenic mice using this technol